This project aims to elucidate immune responses to human and nonhuman primate retroviruses, identify immune correlates of protection, and develop vaccine and immune therapy strategies. Studies of immune selected neutralization resistant human immunodeficiency virus type 1 (HIV-1) variants have shown that these mutants escape via multiple pathways: the CD4 binding region on gp12O; the V3 loop (the principal neutralizing determinant); and other as yet undefined avenues. The variety of escape routes is a serious problem for vaccine development. Persistence of viral variants is also determined by pathogenicity: benign viruses are selected over more virulent ones. Thus, many factors influence the in vivo spectrum of viral variation. Conformation of the viral envelope is crucial to neutralization. Immunization of mice with a chimeric recombinant virus containing the V3 loop of the MN isolate within the HXB2 envelope showed that non-V3 loop epitopes elicited neutralization antibodies. However, a chimeric hemagglutinin-V3 loop envelope construct elicited high-titered, long-lasting neutralizing antibodies in small animals. This HA-HIV chimera may prove useful both as a primary and a booster immunogen. In studies of cellular immunity, HIV-2-specific cytotoxic T-lymphocytes were more readily detected in tissues than peripheral blood of infected rhesus macaques. Thus, tissue sampling may be necessary to assess immune correlates of protection. Attenuated vaccinia-HIV-1, -HIV-2, and -simian immunodeficiency virus (SIV) recombinants prime humoral and cellular immune responses in macaques. Conserved, protective epitopes may exist between HIV-1 and HIV-2, as some macaques immunized with HIV-1 recombinants resisted an HIV-2 challenge. Immunization of macaques with HIV-2 recombinants followed by a subunit booster resulted in protection from infection in 7 of 10 animals. Five of the 7 remained uninfected after a second challenge 6 months later. Animals immunized with SIV recombinants did not resist SIV infection, although their disease course may be altered. Protection from infection seems more closely associated with cellular immunity than with neutralizing antibody.